Interactome analysis reveals ZNF804A, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment.
Interactome analysis reveals ZNF804A, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment.
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DOI：
10.1038/mp.2017.166
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发表时间：
2018-04
影响因子：
11
通讯作者：
Mao Y
中科院分区：
文献类型：
--
作者：
Zhou Y;Dong F;Lanz TA;Reinhart V;Li M;Liu L;Zou J;Xi HS;Mao Y
最近的全基因组关联研究确定了100多个与精神分裂症（SZ）显著相关的遗传位点。一个最佳候选基因ZNF 804A在不同群体中稳健复制。然而，它的神经功能在很大程度上是未知的。在这里，我们表明，在小鼠中，ZFP 804A，ZNF 804A的同源物，是需要正常的祖细胞增殖和神经元迁移。利用酵母双杂交全基因组筛选，我们确定了新的ZNF 804A相互作用蛋白。而不是转录因子，参与mRNA翻译的基因在我们的相互作用组结果中高度代表。ZNF804A与翻译机制共分馏，并调节翻译效率以及mTOR通路。核糖体蛋白RPSA与ZNF804A相互作用并挽救ZNF804A敲低引起的迁移和翻译缺陷。RNA免疫沉淀-RNAseq（RIP-Seq）鉴定与ZFP 804A结合的转录物。因此，ZFP804A与许多参与翻译和线粒体调控的短转录本相关。此外，在与ZFP804A相关的转录物中，SZ风险基因神经颗粒蛋白（NRGN）是ZFP804A的靶标之一。有趣的是，ZFP 804A的下调降低了NRGN的表达，而NRGN的过表达可以改善ZFP 804A介导的迁移缺陷。为了验证ZNF 804A的下游靶标，Duolink原位相互作用测定证实了来自我们的RIP-Seq数据的基因为ZNF 804A靶标。因此，我们的工作揭示了SZ风险基因与神经发育和翻译控制的新机制联系。这里的相互作用组驱动的方法是将全基因组关联发现转化为人类疾病的新生物学见解的有效途径。
Recent genome-wide association studies identified over 100 genetic loci that significantly associate with schizophrenia (SZ). A top candidate gene, ZNF804A, was robustly replicated in different populations. However, its neural functions are largely unknown. Here we show in mouse that ZFP804A, the homolog of ZNF804A, is required for normal progenitor proliferation and neuronal migration. Using a yeast two-hybrid genome-wide screen, we identified novel interacting proteins of ZNF804A. Rather than transcriptional factors, genes involved in mRNA translation are highly represented in our interactome result. ZNF804A co-fractionates with translational machinery and modulates the translational efficiency as well as the mTOR pathway. The ribosomal protein RPSA interacts with ZNF804A and rescues the migration and translational defects caused by ZNF804A knockdown. RNA immunoprecipitation–RNAseq (RIP-Seq) identified transcripts bound to ZFP804A. Consistently, ZFP804A associates with many short transcripts involved in translational and mitochondrial regulation. Moreover, among the transcripts associated with ZFP804A, a SZ risk gene, neurogranin (NRGN), is one of ZFP804A targets. Interestingly, downregulation of ZFP804A decreases NRGN expression and overexpression of NRGN can ameliorate ZFP804A-mediated migration defect. To verify the downstream targets of ZNF804A, a Duolink in situ interaction assay confirmed genes from our RIP-Seq data as the ZNF804A targets. Thus, our work uncovered a novel mechanistic link of a SZ risk gene to neurodevelopment and translational control. The interactome-driven approach here is an effective way for translating genome-wide association findings into novel biological insights of human diseases.
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影响因子：
11.3
作者：
Frazier, JA;AlaghbandRad, J;Rapoport, JL
通讯作者：
Rapoport, JL
影响因子：
4.5
作者：
de Baumont, Angelica;Maschietto, Mariana;Brentani, Helena
通讯作者：
Brentani, Helena
影响因子：
3.5
作者：
Griswold, Anthony J.;Ma, Deqiong;Pericak-Vance, Margaret A.
通讯作者：
Pericak-Vance, Margaret A.
影响因子：
5.3
作者：
Cloutier, Martin;Aigbogun, Myrlene Sanon;Wu, Eric
通讯作者：
Wu, Eric
DOI：
10.1093/cercor/bhm184
发表时间：
2008-07
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Bayatti N;Moss JA;Sun L;Ambrose P;Ward JF;Lindsay S;Clowry GJ
通讯作者：
Clowry GJ